Circulation March 24, 2020

Dr Carolyn
Lam:              
Welcome to Circulation on the Run, your weekly podcast soiree and
backstage pass to the journal and its editors. I'm Dr Carolyn
Lam, Associate Editor for the National Heart Center and Duke
National University of Singapore.


Dr Greg
Hundley:           
And I'm Greg Hundley, Associate Editor from the Pauley Heart
Center at VCU Health in Richmond, Virginia. Well, Carolyn, this
week we're going to talk about carotid stenosis, and you remember
how we measure those a lot with ultrasound, and what that
thickness is, and IMT? Well, we're going to talk about getting
some thresholds and an update in that with our feature discussion
today. But before we get there, how about grab a cup of coffee
and we get started with other papers.


Dr Carolyn
Lam:              
All right. Well, I've got my coffee and I'm ready to tell you
about two papers. They're both on left ventricular hypertrophy.
One is basic and one is clinical. I will start with the basic
paper because it is a super cool one that uncovers a novel
mechanism underlying myocardial hypertrophy. And this involves
S-nitrosylation, a prototypic, redux-based post-translational
modification, S-nitrosylation.


So this is from co-corresponding authors, Drs Xie, Han, and Ji
from Nanjing Medical University, who performed a series of
elegant experiments using myocardial samples from patients and
animal models exhibiting myocardial hypertrophy, and they
demonstrated that S-nitrosylation of muscle limb protein plays a
crucial role in myocardial hypertrophy.


This muscle limb protein modification enhanced binding to
toll-like receptor 3 and receptor interacting protein kinase 3,
which stimulated NOD-like receptor pyrin domain containing 3 or
NLRP3 inflammasome activation and consequent caspace-1 and
interleukin 1 beta activation, ultimately promoting myocardial
hypertrophy. They further showed that the deficiency of
S-nitrosylated muscle limb protein governed toll-like receptor 3
really alleviates pathological myocardial hypertrophy.


Okay Greg, I can see the look on your face. You're like what?
That was a lot. What are the clinical implications, right?


Dr Greg
Hundley:           
Yeah, Carolyn, you are taking me back to molecular biology course
410, that I would take as a senior in college. Wow. So tell me
what are the clinical implications?


Dr Carolyn
Lam:              
All right, here's a take-home. The data really identify that
S-nitrosylated muscle limb protein is a key regulator, which
together with toll-like receptor 3 made therefore serve as
putative therapeutic targets in treating pathological myocardial
hypertrophy in heart failure. That's the take-home. Before any
further comments, let's go to the clinical study.


Now, this one focuses on a malignant subphenotype of left
ventricular hypertrophy in which minimal elevations of cardiac
biomarkers identify individuals with left ventricular hypertrophy
at high risk for developing heart failure. And this is from
corresponding author Dr James de Lemos from UT Southwestern. He
and his colleagues tested the hypothesis that a higher prevalence
of the malignant left ventricular hypertrophy phenotype among
blacks may contribute to racial disparities in heart failure
risk. So they pooled data from three large multi-ethnic cohorts,
that is Eric, Dallas Heart Study, and MESA, totaling more than
15,700 participants. These participants were then classified into
three groups: One, those without ECG left ventricular
hypertrophy; two, those with ECG left ventricular hypertrophy but
normal biomarkers; and three, those with ECG left ventricular
hypertrophy and at normal levels of two biomarkers, high
sensitivity troponin T above six nanogram per liters, or
NT-proBNP above 100 picograms per milliliter. And that last group
were the malignant left ventricular hypertrophy group.


They found that the prevalence of malignant left ventricular
hypertrophy was threefold higher among black men and women versus
white men and women. Compared to participants without left
ventricular hypertrophy, the adjusted hazard ratio for heart
failure was 2.8 in those with malignant ventricular hypertrophy
and only 0.9 in those with left ventricular hypertrophy and
normal biomarkers. And these were similar findings in each race
and sex subgroups.


Mediation analysis indicated that 33% of the access hazard of
heart failure among black men and 11% of the excess hazard among
black women was explained by the higher prevalence of malignant
left ventricular hypertrophy in blacks.


Dr Greg
Hundley:           
So Carolyn, race could be a really important issue in left
ventricular hypertrophy. What did the authors conclude? I mean,
how should this help us perhaps manage these patients? What was
the take-home?


Dr Carolyn
Lam:              
So this really shows that a higher prevalence of the malignant
hypertrophy phenotype may in part, explain the higher risk of
heart failure among blacks compared to whites. And what it means
too is that when left ventricle hypertrophy is detected by ECG or
cardiac imaging, perhaps we should consider measuring high
sensitive troponin T or NT-proBNP, which will help distinguish
those in whom risk for heart failure is favorable from those at a
much higher risk.


Dr Greg
Hundley:           
Very, very interesting. Well Carolyn, I'm going to switch. I've
got a basic paper and it's going to focus on dysfunctional
adipocytes and how they might talk to cardiomyocytes in the
situation of ischemia reperfusion injury. And the corresponding
author is Xin-Liang Ma, from Thomas Jefferson University in
Pennsylvania.


So Carolyn, do you have any thoughts regarding how patients with
diabetes might experience a greater degree of myocardial ischemia
reperfusion injury in the setting of an MI?


Dr Carolyn
Lam:              
Oh my goodness, you're really putting me on this spot here. Well,
I know things that come to mind would be oxidative stress,
microvascular disease.


Dr Greg
Hundley:           
Very good. Open-ended questions for Carolyn's quiz. I'm going to
give you a 90. That was very good. So Carolyn, this current study
attempted to clarify whether and how small extracellular vesicles
may mediate pathological communication between diabetic
adipocytes and cardiomyocytes, exacerbating myocardial ischemia
reperfusion injury. And to do this, adult male mice were fed a
normal or high fat diet for 12 weeks.


The small extracellular vesicles from diabetic serum, diabetic
adipocytes, high glucose, high lipid-challenged, non-diabetic
adipocytes were injected then, intramyocardially, distal of the
site of a coronary ligation.


Dr Carolyn
Lam:              
Okay. So Greg, I would not have guessed it was about
extracellular vesicles, but very interesting. What did they find?


Dr Greg
Hundley:           
Intramyocardial injection of diabetic serum small extracellular
vesicles or these SEVs, in the nondiabetic heart, significantly
exacerbated myocardial ischemia reperfusion injury, as evidenced
by poor cardiac function recovery, larger infarct size, and
greater cardiomyocyte apoptosis. And administration of small
extracellular vesicles, biogenesis inhibitors, significantly
mitigated the myocardial ischemia reperfusion injury in diabetic
mice. And mechanistic investigations in these studies identified
that MIR 130B3P is a common molecule, significantly increased in
diabetic serum of small extracellular vesicles and mediated the
pathological communication between the dysfunctional adipocytes
and the cardiomyocytes. Therefore, if in the future, we could
interfere with this molecule, that could perhaps be a novel
strategy for attenuating diabetic exacerbation of myocardial
ischemia reperfusion injury. Really, a clever study, I think.
What else did you find in this issue of the journal?


Dr Carolyn
Lam:              
Yeah, Greg, this week's issue is packed with other papers too.
For example, there's the research priorities for HFpEF by NHLBI
working group summary by Dr Shah, et al. There's a research
letter by Dr Kaltman on the disparities in congenital heart
disease mortality based on proximity to a specialized pediatric
cardiac center. There's also another research letter by Dr
Irisawa, on the impact of low-flow duration on favorable
neurological outcomes of extracorporeal CPR, after
out-of-hospital cardiac arrest, and this is a multicenter
prospective study.


Dr Greg
Hundley:           
It sounds like a lot's in the mailbag. In the couple of things
that I wanted to talk about, Dr Giulia Rivasi from the University
of Florence, and William White from University of Connecticut,
exchange a series of letters back and forth regarding a previous
publication on the effects of intensive versus standard
ambulatory blood pressure control on cerebrovascular outcomes in
older individuals.


I have another research letter entitled, The Cardiac Cell Therapy
Rejuvenates the Infarcted Rodent Heart via Direct Injection, but
not by Vascular Infusions. And that is from Dr Jeffrey Molkentin
from Cincinnati Children's Hospital Medical Center.


Finally, though Carolyn, there's a very interesting piece from Dr
Carl Bakker at the Ann and Robert H. Lurie Children's Hospital of
Chicago, discussing are we now in a time, in the United States,
where congenital heart surgery should be coalesced or
regionalized? And that really comes on the back of a discussion
of there have been several high-profile articles in the national
media, reporting on US congenital heart surgery programs. And
that's led to, the author describes, some closure of several
centers and at least in five programs. So a great discussion on,
should this be regionalized? But we've got a great feature
article coming ahead and how about if we head to that.


Dr Carolyn
Lam:              
Let's go, Greg.


Dr Greg
Hundley:           
Welcome everyone, to this feature discussion where we are going
to discuss the use of diagnostic ultrasound in the carotid
arteries and how that pertains to selection of patients for
vascular surgery. And with us today, we have Dr Jesse Columbo
from the Geisel School of Medicine at Dartmouth University in
Hanover, New Hampshire. We also have Dr Bob Zwolak, from the
Manchester VA at the Dartmouth School of Medicine and we have our
own Josh Beckman from Vanderbilt University, one of our associate
editors at Circulation. And Bob, let's get started with you.
Could you tell us a little bit, what was the background of this
study and what hypothesis were you looking to test?


Dr Robert
Zwolak:          
It goes without saying that stroke is still a huge health problem
in the United States. If there is any good news, it's that stroke
incidence is falling slightly, but there are still over 100,000
deaths from stroke each year in United States and as many as
700,000 new strokes each year, and a significant proportion of
those derive from atherosclerotic plaque in the carotid
bifurcations.


Carotid duplex ultrasound is a fantastic way to assess the
presence of plaque in the carotid bifurcations because it does
not use any ionizing radiation, does not require any contrast.
Ultrasound is a relatively less expensive technology than CT or
MR, and the study can be repeated so we can follow people over
time, who are found to have significant atherosclerotic plaque in
their bifurcations.


The hypothesis of our study though, was that there is variation
in the diagnostic thresholds used by various carotid ultrasound
testing laboratories, such that it may impact the healthcare and
the treatment plans of people who undergo the studies. Jesse will
tell you the details, but specifically, we hypothesized that
people who undergo this carotid ultrasound test may or may not be
inducted into a surveillance program and intensive therapy based
on the diagnostic criteria that were used by the individuals
conducting their ultrasound study. And even more substantially,
we hypothesized that individuals who undergo carotid
endarterectomy or potentially carotid stenting, could also have
their procedure influenced, whether or not they undergo surgery
or stenting based on the carotid ultrasound results. It might
vary from one facility to another. So it potentially could be
that an individual would be inducted into ultrasound surveillance
or even undergo carotid surgery, depending on the vascular
laboratory in which they were tested.


Dr Greg
Hundley:           
Jesse, could you tell us a little bit, what was your study
population and how did you design this to address the hypothesis
that Bob just stated?


Dr Jesse
Columbo:         
Sure. A review of the published literature really shows a
variability in that ultrasound criteria that's used for
diagnosing carotid stenosis. And so our first objective was to
see if we could obtain as many in-use criteria as possible. Our
first step was to partner with the Intersocietal Accreditation
Commission, the commission that accredits vascular labs. We
partnered with them and obtained a 25% random sample of
ultrasound criteria in use across the US. And so that kind of
gave us the starting point for the criteria upon which to look
at.


We then wanted to apply those to a couple of different groups. As
Dr Zwolak mentioned, there's really two primary breakpoints here.
One, you either have mild stenosis, where you get medical
therapy, but no further surveillance, or moderate stenosis, at
which point you then are dedicated to long-term surveillance per
the AAJ recommendations, or then, the break point between
moderate and severe stenosis where surgery is considered.


What we wanted to do is examine the impact of moderate and severe
stenosis thresholds. For the severe stenosis thresholds, we use
the Vascular Quality Initiative Registry, which collects
information on patients who underwent carotid endarterectomy.
When we studied patients specifically that we thought the percent
stenosis would be the major deciding factor in who got surgery,
those are the asymptomatic stenosis and we applied the range of
severe stenosis criteria from the IAC to those patients. We then
wanted to study other individuals who might be committed to
long-term surveillance based on the criteria used. And so for
that, we used participants in the Cardiovascular Health Study,
which had their induction into the study, had baseline data on
carotid stenosis collected. And so that kind of formed our basis
of the study, applying the criteria to those two different groups
of individuals.


Dr Greg
Hundley:           
And so how many subjects did you have in the two cohorts? And
then tell us what were your study results?


Dr Jesse
Columbo:         
Sure. Once we narrowed down that patients in the vascular quality
initiative to those who underwent surgery for asymptomatic
carotid stenosis, we had about 28,000 patients. And then when we
examined the Cardiovascular Health Study, we had about 4,800 or
5,000 patients in that group. What we found was pretty
interesting.


If you look at individuals who underwent surgery, and you take
the carotid threshold criteria and apply it to them, and if you
say, "Well, we're going to take criteria in the fifth percentile
versus criteria in the 95th percentile," what you'll find is that
10% of patients who got surgery, fall between that range. And
what that means is that there are patients, approximately 10% of
patients, who are undergoing surgery that may not have been
offered surgery if they had gone to a different institution,
which we thought a pretty important finding.


The second part was studying patients who maybe committed to
long-term surveillance. And if we took centers that were in the
fifth percentile versus those in the 95th percentile for their
carotid stenosis thresholds, we found a twofold difference in the
number of patients that would be committed to long-term
surveillance. And remember, this is the difference between
getting aspirin and a statin and medical therapy, but no longer
surveillance and getting carotid ultrasound every six months to a
year for a long period of time. That twofold difference really
could have a meaningful impact on patients.


Dr Greg
Hundley:           
It sounds like we've got a variance issue here and that could
really impact clinical care. So while ultrasound's very portable
and advantageous, how do we use these results to more effectively
select how we're going to implement ultrasound to monitor these
patients?


Dr Joshua Beckman:       I have to
say the results of this study, when I read them the first time
were eye opening. One point that doesn't come out clearly to
those folks who aren't necessarily in the field, is that these
are the labs that have been accredited and they are the top labs
in the United States. This doesn't include at least half of the
rest of the labs in the United States and suggest that if there's
variation in the very best of labs, you know that there's even
more variation that's being practiced routinely around the United
States. So when I read this, I thought that there was a huge
problem that they were uncovering. There are many, many millions
of patients with atherosclerosis.


And so what we have to figure out now is how to standardize the
measurement and reading of these studies so that ultrasound can
be deployed routinely, without a fear of your treatment varying
based on which doctor you decide to see and where you decided to
go. And I think the fact that these guys highlighted that in such
a nice and clear way, really raises the alarm and raises the flag
that attention needs to be paid here quite soon because it's
quite important.


Dr Greg
Hundley:           
So what study could we perform next? And maybe I'll ask, Bob, you
just start off. What study could we perform next to help clarify
and guide us to the better use of ultrasound in this situation?


Dr Robert
Zwolak:          
Well, I think there are two issues. The first issue that this
manuscript points out is the one of variation and it's real and
the results speak for themselves. The second issue is the one of
accuracy, and the question of what are the best thresholds? And
there are several ways that this can be standardized. I'm pleased
to say that the Intersocietal Accreditation Commission, the IAC,
that Jesse mentioned, is actually tackling this problem.


Dr Robert
Zwolak:          
But what's the gold standard? 40 years ago when ultrasound was
developed, these thresholds that people are discussing, were
related to measurements on contrast arteriograms. And the
catheter-based contrast arteriogram, a relatively invasive study,
was the source and we compared ultrasound velocities to the
measurements on the contrast arteriograms to determine these
thresholds that Jesse has investigated. That resulted in
substantial variation depending on the individual authors. The
question is, over time, have the machines changed? Is there
really a central focus that we can look at? Most of these studies
were very small and so it accounts for the variation in
recommendations.


Dr Robert
Zwolak:          
The IAC now, is going back and collecting contemporary contrast
arteriograms, not so many of which are done anymore and so, it's
taken a very substantial multicenter effort. But trying to look
again, to see if there are more accurate results that could be
published, studied in a way such that they would be universally
accepted and potentially promulgated by professional societies
within guidelines. And standardized such that various
specialties, whether it's vascular surgeons who run the labs, or
a cardiologist, or radiologist, would agree on a set of both
accurate and reproducible and constant velocity thresholds to
standardize this technology, which is otherwise a very, very good
technology and eliminate this variation that we've seen.


Dr Greg
Hundley:           
Well, this has been a phenomenal discussion in a very interesting
piece of research. Jesse, can you give us sort of a point forward
from here, how do we move forward with some of these results and
what you anticipate seeing going forward?


Dr Jesse
Columbo:         
Well, a duplex ultrasound for carotid stenosis is really
important. There are lots of studies done. It's a great way to
follow patients over time, in a noninvasive manner. And I might
hope that this paper would open the eyes of some of the listeners
as to what the carotid ultrasound really means. Instead of just
looking at the percent stenosis on the report, to perhaps look at
the raw velocities and interpret them in the context of the
patient, because I think that has really important impact on how
we might manage some of these individuals, for each person that
you see.


Dr Greg
Hundley:           
Well, listeners, we want to thank Dr Jesse Columbo, Dr Bob
Zwolak, also Dr Josh Beckman, for discussing this very
informative research related to the use of ultrasound for
assessing carotid stenosis.


Dr Greg
Hundley:           
On behalf of both Carolyn and myself, we wish you a great week
and see you next week. This program is copyright, the American
Heart Association 2020.